Project Summary/Abstract Alzheimer's Disease is the leading cause of dementia and is pathologically characterized by extracellular amyloid plaques, tau protein aggregates in the brain, and microgliosis. Microglia are the resident innate immune cells of the central nervous system (CNS) and recent genome-wide association studies have linked mutations in microglial genes to increased risk of developing late-onset Alzheimer's Disease. One of the main functions of microglia is phagocytic clearance of debris including extracellular tau, and microglia uptake of tau has been implicated in tau pathology. Therefore, a deeper understanding of microglial phagocytosis and its regulation in disease is necessary to understand the mechanism of tau aggregation in Alzheimer's Disease and to identify new therapeutic targets. MicroRNAs (miRNAs) are small, non-coding RNAs that inhibit translation of their target mRNAs, and their expression has been shown to be dysregulated in AD patients with some of these miRNAs targeting innate immune pathways. It is, however, not well understood what miRNAs in microglia modulate cell function and whether microglial miRNAs can modulate tau pathology. Our preliminary studies show that loss of mature miRNAs in microglia exacerbates tau pathology in male tauopathy mice. We hypothesize that loss of miRNAs in microglia decreases the cell's ability to degrade tau, leading to increases in extracellular tau, and exacerbating aggregation of tau in neurons. In this proposal, we outline two aims to test this hypothesis. In Aim 1, we will test the hypothesis that loss of mature miRNAs in microglia decreases the cell's capacity to degrade tau in vitro and in vivo. In Aim 2, we will test the hypothesis that the most highly-expressed miRNA in microglia, miR-16-5p, is necessary and sufficient for degradation of tau by microgila and can modulate tau pathology in vivo. These experiments will shed insight onto miRNA- regulation of tau phagocytosis and degradation and its contribution to tau aggregation. Completion of these aims will yield insights into new pathways regulating the innate immune system in tauopathies and uncover potential targets for miRNA-based therapeutics in Alzheimer's Disease.